tbuckley/cabot-search huggingface dataset:
Effect of reducing the number of neoadjuvant chemoimmunotherapy cycles on clinical efficacy in locally advanced PD-L1 positive gastric cancer: A single center phase 2 study.
Authors: Lingdi Zhao, Zhiqiang Jiang, Jinxi Huang, Zhimeng Li, Qiang Fu, Yingkun Ren, Yuzhou Zhao, Bin Zhang, Xiangbin Wan, Chuang Shang, Ye Kong, Jialin Liu, Zhi Li, Quanli Gao
Journal: Journal of Clinical Oncology (2023)

e16074 Background: The standard therapeutic recommendation is neoadjuvant chemotherapy with FLOT regimen following radical resection in patients with locally advanced gastric cancer. It is not clear whether neoadjuvant anti-PD-1 antibody plus FLOT regimen could improve the pathological complete response (pCR) rate and how to combine anti-PD-1 antibody and FLOT regimen. We conduct this phase II study to explore this problem (NCT 04891016). Methods: This study is a prospective clinical study, patients are randomly enrolled into the experiment group and the control group according to the random number method. The patients in the experiment group receive standard dose of FLOT regimen plus toripalimab every three weeks, toripalimab is administered on third day in each cycle, after three cycles operation is performed. The patients in the control group receive standard dose of FLOT regimen plus toripalimab every two weeks, toripalimab is administered on the first day in each cycle, after four cycles operation is performed. The primary endpoint is pCR and the secondary endpoint is recurrence-free survival. Results: From June 2021 until present, 57 patients with locally advanced gastric cancer were enrolled in this study, including 28 patients in the experiment group and 29 in the control group. Three patients in the experiment group and two in the control group withdrew from the study as to the influence of COVID-19’s epidemic or personal reason. One patient in the experiment group postponed operation due to immune-related thrombocytopenia. The remaining 51 patients completed the prescribed chemotherapy plus toripalimab and operation, and all the operations were R0 resection. Among these 51 patients, pCR was got in 16 patients and the pCR rate was 31.4%, MPR rate was 66.7%. Further analysis according to the expression of PD-L1 is shown. The overall incidence of adverse events was 93%. The incidence and severity of myelosuppression in the experiment group were lower than those in the control group. Among all the patients received R0 resection, 6 patients experienced recurrence and the remaining are still kept in recurrence-free status. The recurrence-free survival is not available at present. Conclusions: 1) Neoadjuvant therapy with FLOT plus toripalimab is safe and effective in locally advanced gastric cancer. 2) Postponing the use of toripalimab when combined with FLOT as neoadjuvant regimen in locally advanced gastric cancer patients with PD-L1 CPS ≥1 could reduce the number of chemotherapy cycles and thus reduce the adverse events of chemotherapeutic drugs, while the dose intensity of chemotherapy is import in patients with PD-L1 CPS ＜1. Clinical trial information: NCT04891016 .[Table: see text]
Effect of multi-omics analysis on tumor ecosystem during neoadjuvant dose-limiting chemotherapy combination with sequential PD-1 blockade for patients with esophageal cancer.
Authors: Qi Song, Bo Yang, Qi Xiong, Zhanbo Wang, Yaping Long, Zhouhuan Dong, Wenhao Zhou
Journal: Journal of Clinical Oncology (2023)

e16085 Background: Patients with esophageal cancer benefited from neoadjuvant chemotherapy combined with immunotherapy. However, the sequence of administration during neoadjuvant therapy remains under considerable debate. Methods: A study on 23 enrolled patients with esophageal cancer who received 2 cycles of neoadjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab and 2 cycles of adjuvant treatment of dose-limiting chemotherapy combined with sequential pembrolizumab was carried out. Serial plasma samples were collected and subjected to T cell receptor (TCR) sequencing. Tissues with pre- and post-neoadjuvant therapy were obtained and performed with whole-exome sequencing and transcriptome sequencing. Results: After neoadjuvant therapy, the percentage of patients with a pathological major response (MPR) was 39.1% (9/23), consisting of 21.7% (5/23) completed pathological response (cPR). TCR sequencing analysis showed that the peripheral blood-dominated TCR clones significantly augmented during the neoadjuvant treatment. Tumor mutational burden (TMB) was higher in the MPR group than in the non-MPR group at baseline. In addition, infiltrating CD8+ T cells increased and regulatory T (Treg) cells decreased in the MPR group after neoadjuvant therapy. While Treg cells increased in the non-MPR group after neoadjuvant treatment. Conclusions: Dominated TCR clones increased during the neoadjuvant limited-dose chemotherapy stage, which would contribute to sequential PD-1 blockade. Additionally, TMB, CD8+ T cells, and Treg cells are associated with clinical benefits during treatment.
First report of ELUCIDATOR study: A prospective observational multicenter study on resistance mechanisms in patients with early disease progression during osimertinib.
Authors: Yasuyuki Mizumori, Akihiro Tamiya, Mitsuo Osuga, Shun-ichi Isa, Yoshihiko Taniguchi, Keiichi Nakamura, Daijiro Harada, Tsutomu Shinohara, Hidetoshi Yanai, Katsumi Nakatomi, Masahide Oki, Masahide Mori, Tomohito Kuwako, Koji Yamazaki, Atsuhisa Tamura, Masahiko Ando, Yasuhiro Koh
Journal: Journal of Clinical Oncology (2023)

3032 Background: Osimertinib (Osi) is the key standard therapy for patients (pts) with chemo-naive advanced non-small cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor ( EGFR) mutations. However, many of cases treated with Osi experience the disease progression (PD). Therefore, understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies. Here, we addressed the underlying mechanisms of resistance to Osi using paired plasma DNA samples and particularly focused on early PD (PD within 6 months) cases. Methods: This trial is the multicenter prospective research, and we prospectively collected plasma DNA samples prior Osi treatment and at PD. Next-generation sequencing (NGS) implemented with the molecular barcoding method was performed to analyze gene mutations in 197 cancer-associated genes. Then using these ct-DNA, we analyzed the Osi resistance by ultra-sensitive NGS. In this interim analysis, we specially analyze the early PD (PD within 6 months) cases. Results: One hundred eighty-eight pts were enrolled between May 2019 and January 2021. Among these pts, 125 (66%) pts were female, 96 (51%) were EGFR exon 19 deletion mutation, and 109 (58%) were never smoker. Seventy-eight pts experienced PD and 36 pts experienced early PD at interim analysis. Baseline shedders, patients with plasma positivity for EGFR-activating mutation were more frequently observed in early PD pts than non-PD (86.1% vs 63.4%, p = 0.009). Early PD patients had significantly more co-occurring gene mutations along with EGFR mutations than non-early PD patients (2.89±1.49 vs 1.97±1.37, p = 0.002). Most notably, 3 among 36 early PD pts and 8 among 78 PD pts had significant reduction of plasma EGFR mutant allele frequency at PD than that at baseline. Among those, 1 had germline BRCA1 mutation and 1 had BRINP3 mutation in 3 early PD pts, and 1 had germline BRCA2 mutation, and 1 had germline TP53 mutation in 5 PD pts excluding early PD pts. Co-occurring TP53 mutations were not relevant to early PD in this study cohort. Conclusions: Germline mutations in BRCA1/2, TP53 and BRINP3 may confer early and unprecedented resistance to Osi monotherapy. Plasma-based serial comprehensive gene profiling may help predict and identify patients unlikely to benefit from Osi treatment, though further study is warranted. Clinical trial information: jRCTs031180051 .
Clinical performance of Bladder EpiCheck methylation test for active surveillance of non-muscle invasive bladder cancer: Systematic review and meta-analysis.
Authors: YUANPING HSIA, Cho Hsien Chiang, Cho Han Chiang, Cho Hung Chiang, Shih-Syuan Wang, Yu-Cheng Chang, Aunchalee Jaroenlapnopparat, Her-Shyong Shiah
Journal: Journal of Clinical Oncology (2023)

e16597 Background: Non-muscle invasive bladder cancer (NMIBC) has a favorable 5-year survival, but up to 60% of patients experience cancer recurrence within the first year of diagnosis. The current gold standard for active surveillance is periodic cystoscopy, but this is expensive and invasive. An alternative non-invasive method involves urine cytology, but it has poor sensitivity. Recently developed urine-based molecular diagnostics such as the EpiCheck (Nucleix, Rehovot, Israel) test offers non-invasive and quick testing for active surveillance. In this systematic review and meta-analysis, we aimed to evaluate the diagnostic value of Bladder EpiCheck in active surveillance of NMIBC. Methods: We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies published between 1 January 2010 and 31 December 2022. The primary outcome was the sensitivity / negative predictive value (NPV) and specificity (PPV) of Bladder EpiCheck in active surveillance of NMIBC. We also performed a subgroup analysis to evaluate the performance of EpiCheck in detecting the recurrence of high-grade and low-grade NMIBC. Results: Our systematic search identified 110 articles, from which 6 studies were included in the final analysis. Compared with urine cytology, EpiCheck had a higher pooled sensitivity (73% [95% CI: 59-83] vs. 51% [95% CI: 30-72]) and NPV (90% [95% CI: 79.5-95.2] vs. 84% [95 % CI: 69-92]. However, EpiCheck had a lower pooled specificity (63% [95% CI: 48-76] vs. 97% [95% CI: 89-99]) and PPV (63% [95% CI: 48-76] vs. 85% [95 % CI: 69-94] than urine cytology. Similarly in subgroup analysis, EpiCheck had a higher pooled sensitivity than urine cytology in detecting both high-grade (86% [95% CI: 78-91] vs. 63% [95% CI: 43-80]) and low-grade (44% [95% CI: 34-55] vs. 13% [95% CI: 7-23]) NMIBC. Conclusions: The Bladder EpiCheck test has a better sensitivity than urine cytology and may be utilized as a part of the active surveillance strategy for NIMBC recurrence.
Debio 0123-101: A phase 1 trial of Debio 0123 in combination with carboplatin in advanced solid tumors—Safety, pharmacokinetic, and preliminary antitumor activity data.
Authors: Hans Gelderblom, Mathilde Jalving, Ingrid Desar, Omar Saavedra, Jourik A. Gietema, Stefan van Ravensteijn, Nina Ajmone Marsan, Anne Bellon, Sandrine Micallef, Noemie Luong, Luke Piggott, Rikke Frederiksen Franzen, Esteban Rodrigo Imedio
Journal: Journal of Clinical Oncology (2023)

3012 Background: Cell cycle faults are typical in cancer, with tumor cells depending on G2 checkpoints to avoid excess DNA damage. WEE1, a DNA damage-activated kinase, governs G2 by phosphorylating cyclin-dependent kinase 1 (CDK1) to arrest the cell cycle and permit DNA repair. Via CDK1 inhibition, WEE1 also blocks replication initiation, limiting oncogene-induced replication stress. WEE1 inhibition, with accumulating DNA damage, can induce mitotic catastrophe and apoptosis. Debio 0123, an orally available, ATP-competitive WEE1 inhibitor, is being studied as monotherapy and in combination with carboplatin (CP) in patients (pts) with solid tumors. Here, we report safety, pharmacokinetic (PK), pharmacodynamic, and antitumor activity data for the combination. Methods: Debio 0123-101 (NCT03968653) is a two-arm dose-escalation study in pts with advanced solid tumors that recurred or progressed after receiving platinum-containing therapy, where no standard therapy of proven benefit is available. In Arm A, Debio 0123 was given as monotherapy in cycle (C) 1 (as a single dose on day [D] -3 and once daily over D1–3) and in combination with CP from C2 until end of treatment (EOT). In Arm B, Debio 0123 was given in combination with CP on D1–3 and D8–10, from C1 to EOT. CP was given on D1 of each 21-day cycle in both arms. Skin biopsies were taken at baseline and C1D3 to assess target engagement (TE). Results: Arm A data (cut-off 31.12.2022) is shown. Overall, 38 pts were treated (78.9% female, mean age 58.5 years), with two pts ongoing. Using a continual reassessment method-guided dose escalation, tested Debio 0123 doses ranged from 30–520 mg. The maximum tolerated dose was declared at 520 mg. At this dose level, 2/6 pts experienced a dose-limiting toxicity. The treatment was deemed well tolerated, with a manageable safety profile in line with that expected for CP monotherapy. Most Debio 0123-related toxicities were grade 1/2. Preliminary PK data indicate that Debio 0123 plasma levels rise proportionally with dose. TE was seen from the 150 mg dose, becoming more pronounced with increasing dose levels. Confirmed partial responses (PR) occurred in 5/30 evaluable pts; 4/12 pts with platinum-resistant ovarian cancer achieved a PR (one ongoing). Conclusions: Debio 0123, combined with CP, has a manageable safety profile and is well tolerated up to 520 mg; this combination led to observable antitumor activity in pts with platinum-resistant cancer. Further study of Debio 0123 as a therapeutic agent is warranted. Clinical trial information: NCT03968653 . [Table: see text]
The clinical feasibility of circulating tumor DNA alterations in patients with advanced hepatocellular carcinoma.
Authors: Gwangil Kim, Sohyun Hwang, Haeyoun Kang, Jaekyung Cheon, Beodeul Kang, Chan Kim, Hong Jae Chon
Journal: Journal of Clinical Oncology (2023)

4110 Background: Need for individualized treatment based on tumor attributes is being reinforced with the rapid development of targeted therapies and immune checkpoint inhibitors for hepatocellular carcinoma (HCC). Lack of mandatory tissue biopsy for the diagnosis of HCC, continues to be a challenge for development of precision medicine for HCC compared to other solid tumors. Liquid biopsy enables comprehensive genomic profiling of circulating tumor DNA (ctDNA) shed from tumors into the circulation. This could compensate for the lack of tissue-based analysis in HCC providing a non-invasive and safer option for genomic profiling. This study aims to address the concordance between commercially available ctDNA and tissue genomic profiling in patients with advanced HCC and to assess the feasibility of liquid biopsy in the treatment of patients with HCC. Methods: Patients subjected to tissue-based next-generation sequencing (NGS) before systemic therapy for advanced HCC at CHA Bundang Medical Center from June 2020 to October 2022 and also had sufficient plasma samples available for ctDNA analysis were included. Oncomine Comprehensive Assay (OCA) ThermoFisher was used for tissue-based NGS and Guardant360 for ctDNA based NGS. For the concordance assessment for the same patient, paired samples of ctDNA and tumor tissue, we investigated the common targeted regions across both the panels. Results: Out of hundred thirty patients included in this study, 98% percent of ctDNA samples for these patients were successfully sequenced; ctDNA were detected in 88% of the samples. For the assessment of concordance between intra-patient ctDNA and tumor tissues, we investigated only clinically important (AMP/ASCO/CAP guidelines tier 1 or 2) variants. When we considered the variants detected in tissues as true positive, the concordance between the mutations detected from ctDNA and tissue samples indicated 68.9% sensitivity and 63.1% positive predictive value (PPV). In ctDNA, targetable alterations were detected in 16.9% of samples, such as ARID1A mutations (7.7%), PTEN mutations (6.9%), PIK3CA hotspot mutations (1.5%), RAS mutations (1.5%), and one RET fusion (0.8%). Regarding the concordance between ctDNA and tumor tissue, the sensitivity for mutation was high for RAS mutation (100.0%), PTEN mutations (100.0%), and ARID1A mutations (75.0%) but low for PIK3CA hotspot mutations (0.0%). One RET fusion was identified only in ctDNA. Conclusions: ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue genomic profiling in patients with advanced HCC. Thus, liquid biopsy using ctDNA help address any challenges associated with the limited use of tissue-based genomic profiling in HCC. Investigation of time between blood and tissue collection and the impact it has on concordance is ongoing.
Portal hemodynamic effects of different TKIs in patients with advanced hepatocellular carcinoma: A prospective cohort study.
Authors: Pingping Li, Tao Yan, Jiamin Cheng, Linzhi Zhang, Caiyun Peng, Guodong Su, Yinyin Li, Yinying Lu
Journal: Journal of Clinical Oncology (2023)

e15126 Background: Tyrosine kinase inhibitors (TKIs) are considered to have effects on portal collateral circulation with portal hypertension. According to previous small sample clinical reports, short-term administration of sorafenib might have an effect of decreasing portal venous pressure, while lenvatinib aggravated portal hypertension. Long-term effects of TKIs on portal pressure are still unclear. Therefore, We conducted a prospective cohort study to explore the efficacy of different TKIs for portal circulation in patients with advanced hepatocellular carcinoma. Methods: 27 Child-Pugh class A or B patients with advanced HCC were enrolled in this study, 13 patients received lenvatinib, 7 patients sorafenib, and 7 patients regorafenib. Changes of portal hemodynamic parameters were measured by duplex Doppler ultrasonography, including portal venous area (PVA), portal venous flow velocity (PVV) and congestion index (CI) before and after administration of TKIs for an average 40-50 days. Results: In both regorafenib and sorafenib cohorts, PVA decreased after treatment, although the difference was not significant. PVF significantly reduced in sorafenib cohort (24.96±5.60 vs. 15.46±4.50, P= 0.014) and regorafenib cohort (21.43±2.09 vs. 16.01±1.28, P= 0.024), therefore CI significantly increased in sorafenib cohort (0.060±0.042 vs. 0.088±0.040, P= 0.046) and regorafenib cohort (0.068±0.032 vs. 0.090±0.030, P= 0.043). In lenvatinib, both PVA and PVF have no significant change, while CI increased significantly (0.057±0.027 vs. 0.074±0.040, P= 0.030). Conclusions: In this study, TKIs showed different effects on portal hemodynamic change in advanced HCC. Large sample and long time follow-up research will be necessary to verify their clinical and mechanism effects. [Table: see text]
Reporting of patient reported outcomes in randomized clinical trials (RCTs) in non-small cell lung cancer (NSCLC) patients (pts).
Authors: Laura Palmeri, Sergii Derkach, Ewelina Mazur-Janik, Arundhati Soman, Catarina Ribeiro Alves, Radhika Shah, Liat Vidal-Fisher, Nahid Shahmarvand
Journal: Journal of Clinical Oncology (2023)

6573 Background: A patient-centric approach to clinical trials has become necessary, with regulators emphasizing the importance of pts' experience. PRO is of utmost relevance for pts with cancers such as NSCLC, that are likely to be highly symptomatic and/or with an unfavorable prognosis. Methods: To evaluate the rate at which PRO included in clinical trials are made publicly available when trial results are published, we searched Citeline Trialtrove, a registry of clinical trials, for NSCLC phase 3 RCTs, recruiting during 2017-2022, with PRO listed - regardless of publication type. We excluded supportive care, radiotherapy, and unpublished trials. We identified publications associated with the trial, and extracted various parameters, including if PRO outcome was published. Results: Of 122 NSCLC RCTs identified, 66 listed at least 1 PRO. Trials were reported as full-text (43), abstract (9), 1 only in a trials registry; 13 not published. Fifty-three trials were included, all had PRO as a secondary endpoint. The sponsor was industry in the majority of the trials. Most included stage III/IV NSCLC pts, and 1 st /2 nd line or maintenance. 24 PRO tools were used, mainly EORTC QLQ LC13 (35 trials), EORTC QLQ C30 (34), EQ-5D-5L (14), LCSS (8), EQ-5D-3L (6). Seven trials listed 1 tool, 26 listed 2, 18 listed &gt;3. PRO was reported in 36 (68%) of the published trials. In the subgroup of trials with disease control (DC) benefit and no overall survival (OS) benefit, PRO was reported in 15/21 (71%) trials. PRO benefit was shown in 9 of them. Of 43/53 trials published as full-text, 31 (72%) had PRO reported. A benefit in at least 1 PRO tool was reported in 21 studies, 9 did not show a PRO benefit; in 5 trials, only descriptive and no comparative analysis of PRO was reported. Of the 21 trials with PRO benefit, 19 had a DC benefit and 10 had also OS benefit. PRO was reported together with the first reporting of other outcomes in 18 (50%) trials, and after 7-32 months after the initial one in 18 trials. Conclusions: Of 122 RCTs only 66 had at least 1 planned PRO, and only 35 had it published. Even where full-text was available or no OS benefit shown, about 1/3 of the trials did not report PRO. Characteristics as disease stage, therapy line, sponsor, and primary endpoint did not differ between all included trials and those reporting PRO. The reporting rate increased compared to our previous report yet it is not satisfactory. The importance of quality of life and pts centric outcomes, and the great efforts needed from pts and operators to collect the data, should translate into routine, timely and appropriate reporting of PRO to allow a thorough assessment of treatment effect. [Table: see text]